1. Field of the Invention
This invention relates to a process for forming 10-keto derivatives of morphinan compounds.
2. Description of the Related Art
Methods have been reported in the literature for the synthesis of a small number of structurally related 10-ketomorphinans. Methods using CrO.sub.3 as an oxidant (S. Archer et al., J. Med. Chem. 28: 974-976, 1985, and H. Rapoport et al., J. Am. Chem., 77:4330-4335, 1955) suffer from extremely low yields. Methods which use SeO.sub.2 as oxidant (R. T. Uyeda et al., Tetrahedron Lett., 30:5725-5728, 1989) necessitate rendering the ring nitrogen into a non-basic amide form, thereby adding extra synthetic steps. Commonly used methods for effecting 10-oxidations use a phenolic 3-methyl ether protected analog. The classical conditions for morphinan 3-methyl ether synthesis require the highly toxic, rather volatile dimethyl sulfate in aqueous NaOH (S. Archer et al., J. Med. Chem. 28: 974-976, 1985, and H. Rapoport et al., J. Am. Chem., 77:4330-4335, 1955).
Cerium ammonium nitrate (CAN) has been reported to effect benzylic oxidations on electron rich aromatic compounds in alcoholic (or HOAc) solutions to provide benzyl ether (or acetate) mono adducts (K. Isobe et al., Chem. Pharm. Bull 42: 197-1994). It is therefore an object of the present invention to apply these principals to find a useful oxidation scheme to provide the benzylic 10-hydroxyl adduct. Although CAN has been reported under certain conditions to oxidize simple toluenes to aldehydes and ketones (S. B. Lang et al., J. Chem. Soc. (C)2915, 1968 and references therein), no 10-keto adduct was observed by .sup.1 H NMR in the crude oxidation product. The 10-(S)-alcohol was readily oxidized into the 10-ketone analog with the Dess-Martin periodinane (Dess, D. B. and Martin, J. C., J. Org. Chem. 48, 4155-4158, 1983; Dess, D. B. and Martin, J. C., J. Am. Chem Soc. 113, 7277-7287, 1991; Ireland, R. E. and Liu, L., J. Org. Chem. 58, 2899, 1993; Schrieber, S. L. and Meyer, S. D., J. Org. Chem. 59, 7549-7552, 1994). These pharmaceutical compounds are related to morphinans which have effects such as analgesia, sedation, mood alteration. The 10-keto morphinan compounds are the degradation products of morphinans and may therefore be related to the age and condition of the original morphinan compounds.
It is therefore an object of the present invention to provide a new and rapid method for the conversion of morphinan compounds into their 10-keto analogs. A further object of the invention is to provide a process which provides relatively high yield of the desired compounds. Another object is to provide a method that is relatively safe and avoids the use of highly volatile and toxic reagents.